It is thought that nicotine is one of the main psychoactive ingredients in tobacco smoke that leads to habitual tobacco smoking in humans. Nicotine induces pleasurable euphoric-like effects and also enhances the effects of other rewarding stimuli (i.e., reward facilitation). Further, adaptations induced by chronic nicotine administration result in deficits in brain reward function and somatic signs during nicotine withdrawal. These three effects associated with nicotine consumption (i.e., pleasurable effects of acute nicotine, nicotine- induced facilitation of other rewards, and the aversive nicotine withdrawal syndrome) are all hypothesized to provide important sources of motivation that perpetuate the deadly tobacco smoking habit. The goals of the proposed project are threefold. Specific Aim 1 will attempt to identify specific nicotinic acetylcholine receptor (nAChR) subunits critically involved in the primary reinforcing effects of nicotine. Specific Aim 2 will attempt to identify nAchR subunits critically involved in the reward enhancing effects of acute nicotine. Finally, Specific Aim 3 will attempt to identify specific nAChR subunits which are critically involved in the brain reward function deficits and somatic signs associated with nicotine withdrawal. The proposed studies will be carried out in wildtype mice and genetically modified mice in which a7 or [unreadable]4 nAChR subunits have been null mutated or in which a 4 nAChR subunits have been rendered hypersensitive to nicotine (a7-/-, [unreadable]4-/-, and Leu9'Ala mice, respectively). These subunits have been selected because their localization implicates them in the effects of nicotine investigated in the proposed studies. To identify nAChR subunits critical to the various aspects of nicotine dependence, intravenous nicotine self-administration and intracranial self-stimulation (ICSS) procedures will be utilized. Nicotine self-administration and nicotine- induced lowering of ICSS thresholds will serve as measures of the reinforcing effects of nicotine and nicotine-induced facilitation of reward, respectively. Elevations of ICSS thresholds (i.e., reward deficits) and increased somatic signs of withdrawal during spontaneous nicotine withdrawal will serve as measures of the affective and somatic components of nicotine withdrawal, respectively. These studies will determine whether nAchRs containing the a7, [unreadable]4 and/or a4 subunits are critically involved in mediating effects of nicotine that are hypothesized to be crucial motivating factors in maintaining the tobacco smoking habit. Full nicotine dose-response functions will be generated. Future work will use additional mutant mice to investigate the potential role of other nAchR subunits in the same phenomena. Relevance: Improved understanding of the neurobiological substrates that underlie the rewarding effects of nicotine, the reward-enhancing effects of nicotine and the aversive effects of nicotine abstinence will provide insights into the sources of motivation that result in persistent use of tobacco in humans, and is likely to lead to new and improved behavioral and pharmacological treatments to assist smokers in quitting.